ADCs with maytansine derivatives as cytotoxic agents have been highly favored by researchers and a series of breakthroughs have been achieved. DM1, DM4 are maytansinoids as ADC payloads.

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Maytansinoids as Payloads of ADCs: DM1, DM4
In recent years, antibody-drug conjugates (ADCs) for tumor-targeted therapies have
received great attention; among them, ADCs with maytansine derivatives as cytotoxic
agents have been highly favored by researchers and a series of breakthroughs have been
achieved.
ADC: Composition and Mechanism of Action
More than 100 years ago, researchers proposed the concept of "magic bullets" for
antibody-targeted cancer treatment. As antibody technology continues to mature, there
has been a global boom in the development of ADCs, which are composed of three major
components: antibodies, linkers and toxin warheads.
Figure 1. Rational design of ADCs components. Source: Reference [1]
ADCs specifically recognize tumor antigens and form ADC-antigen complexes to enter
target cells through receptor-mediated cytocytosis, further releasing highly active warhead
molecules to complete the selective killing of tumor cells.
Maytansinoids as Payloads of ADCs

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Maytansine and its derivatives (generally named maytansinoids), a 19-member ansa
macrolide structure attached to a chlorinated benzene ring, were originally isolated from
the shrub Maytenus ovatus. It is a potent microtubule-targeting compound that induces
mitotic arrest and kills tumor cells at subnanomolar concentrations. It showed potent
anticancer activity in human nasopharynx carcinoma KB cells (EC-8 PM), murine
lymphocytic leuke- mia P-388 cells (EC 50-0.6 PM), and murine leukemia L1210 cells (EC
50-2 PM).
However, due to the narrow therapeutic window and high systemic toxicity of maytansine,
maytansine not an oncological chemotherapeutic agent when used alone and has been
clinically banned from direct use in human therapy. ADCs as targeted therapy might be
a promising approach to address the limitations of single-agent therapy.
Based on the mechanism of action of ADC, its payload is usually a highly cytotoxic small
molecule. Maytansinoids have an in vitro inhibitory activity of up to 1000 times higher than
conventional chemotherapeutic agents (e.g. doxorubicin) against a wide range of tumor
cells, with half maximal inhibitory concentration (IC50) reaching sub-nanomolar levels.
Maytansinoids are more potent in killing actively dividing cells than quiescent cells.
Maytansinoids have good stability and solubility in water, allowing them to couple with
antibodies without breaking down or causing aggregation. However, Maytansinoids does
not possess a suitable functional group to derivatize and enable its coupling to antibodies.
A series of maytansine analogs with disulfide or thiol substituents have been recently
synthesized for covalent attachment to mAbs. Among them, DM1 and DM4 are
currently being studied clinically as ADC payloads.
Figure 2. Structures of maytansine and the maytansine thiomethyl analogs S-methyl DM1
and S-methyl DM4. Source: reference [2]

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Antibody-maytansinoid Conjugates
Now, there are two ADCs with maytansinoid-based payloads approved by the FDA,
Kadcyla and Elahere.
Kadcyla
Kadcyla (Trastuzumab Emtansine, T-DM1), developed by Roche, is
a HER2-targeted antibody-drug conjugate (ADC) which contains the humanized
anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a
maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl]
cyclohexane1-carboxylate).
It was approved by the FDA in 2013 to treat metastatic breast cancer, which was
previously treated with ado-trastuzumab and a taxane.
Figure 3. Structure of Kadcyla
Elahere
Elahere (mirvetuximab soravtansine-gynx) is a first-in-class ADC consisting of a folate
receptor alpha (FRα)-conjugated antibody, a cleavable linker, and the maytansinoid
payload DM4.

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On November 14, 2022, the FDA granted accelerated approval of Elahere for use in adult
patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary
peritoneal cancer who have received one to three prior systemic treatment regimens.
Figure 4. Structure of Elahere, Source: https://doi.org/10.3390/molecules28031038
In addition to the two approved drugs mentioned above, several Antibody-maytansinoid
Conjugates have now entered clinical phase II/III, with warheads still focused on
DM1/DM4, while targets have further expanded to FOLR1, CD37, CD56, CD19, CD138,
Mesothelin, CA6, etc.
Table. Antibody-maytansinoid Conjugates in phase III and phase II development. Source:
Reference [1]

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The above is the brief research and development process of maytansine from being
undruggable with strong activity, narrow safety window, and obvious toxicity to being
successfully applied to clinical treatment as an ADC warhead. In fact, in addition to
maytansine, there are many strong cytotoxic substances used in clinical development,
such as dolastatins, auristatins, calicheamicins, duocarmycins, and camptothecin
derivatives, etc.
And as more and more undruggables have become possible in recent years, many areas
that have been studied for years or even suspended have the potential to become blue
ocean markets. Then, both for the industry and for industry investors, the breakthrough
and rapid development of technology requires extra attention and in-depth research.
Biopharma PEG is a professional PEG supplier. We can provide high-purity PEG
linkers from milligram to kilogram scale in GMP and Non-GMP grade for your
antibody-maytansinoid conjugates development. The use of PEGs as a linker between
the antibody and payload molecules allows for higher ADC loading. PEGs create a
protective shield that wraps the ADC payload from its microenvironment, improving
solubility and stability. Other benefits include reduced aggregation and thus lower
immunogenicity, improved pharmacokinetics, increased circulation time and reduced
toxicity.
References:
[1] Zhao P, Zhang Y, Li W, Jeanty C, Xiang G, Dong Y. Recent advances of antibody-drug conjugates for
clinical applications. Acta Pharm Sin B. 2020;10(9):1589-1600. doi:10.1016/j.apsb.2020.04.012
[2] Lopus M, Oroudjev E, Wilson L, Wilhelm S, Widdison W, Chari R, Jordan MA. Maytansine and cellular
metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to
microtubules. Mol Cancer Ther. 2010 Oct;9(10):2689-99. doi: 10.1158/1535-7163.MCT-10-0644. PMID:
20937594; PMCID: PMC2954514.
[3] Wang, Jeffrey & Shen, wei-chiang & Zaro, Jennica. (2015). Antibody-Drug Conjugates: The 21st
Century Magic Bullets for Cancer. 10.1007/978-3-319-13081-1.

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